I plan to study the pathogenesis of Salmonella infections using classical and molecular genetics. My long term goal is the development of a live Salmonella vaccine that can be used as a carrier to deliver heterologous antigens to the immune system. Phase I of this grant includes formal coursework in basic science necessary to study pathogenic bacteria and develop live attenuated bacterial vaccines. Phase I research training will be spent in the laboratory of Dr. John Mekalanos studying the molecular pathogenesis of Salmonella infections. Our preliminary investigations demonstrate that Salmonella typhimurium mutants deficient in the gene regulating acid phosphatase production (phoP) have reduced virulence in a mouse model of typhoid fever. We plan to investigate the cause of this reduced virulence. We also plan to identify S. typhimurium genes important to virulence by the use of several techniques including transposon mutagenesis to create gene translational fusions to E. coli alkaline phosphatase. We also plan to develop a vector delivery system for rapid and stable insertion of genes encoding heterologous antigens on the Salmonella chromosome.